Antisense oligonucleotide targeting CD39 improves anti-tumor T cell immunity

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Cancer cells evade immune responses by converting immune-stimulating ATP to adenosine via CD39 and CD73.
• CD39 is expressed on immune cells and cancer cells, aiding tumor immune evasion.
• Reducing adenosine and increasing ATP can enhance anti-tumor immunity.

Purpose of the Study:

• To develop and evaluate locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CD39.
• To assess the efficacy of CD39-specific ASOs in reducing CD39 expression and restoring anti-tumor immunity.
• To investigate the therapeutic potential of CD39 ASOs in preclinical cancer models.

Main Methods:

• Designed LNA-modified ASOs targeting human and mouse CD39.
• Investigated ASO knockdown efficacy on mRNA and protein levels in cancer cell lines and primary T cells.
• Assessed effects on extracellular ATP levels, T cell proliferation, and in vivo anti-tumor immune responses in mouse models.

Main Results:

• CD39-specific ASOs suppressed CD39 expression in cancer cells and T cells.
• ASO treatment reduced extracellular ATP degradation and enhanced CD8+ T cell proliferation.
• In vivo, CD39 ASOs decreased regulatory T cells (Tregs) and increased the CD8+ T cell to Treg ratio in tumors.
• Combination therapy with anti-PD-1 treatment resulted in significant tumor growth reduction.

Conclusions:

• Targeting CD39 with ASOs is a promising therapeutic strategy to enhance anti-tumor immunity.
• CD39 ASOs can modulate the tumor microenvironment to favor immune-mediated tumor destruction.
• This approach holds potential for improving cancer treatment outcomes, particularly in combination therapies.